Human stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities for studying human disease specific/ personalized models, and provide a personalized renewable source of cells for practical autologous cell therapies, regenerative medicine, and predictive toxicology applications. Studies outlined in this proposal are designed to explore application of CiPSC for the generation of personalized cardiomyocytes which can be used for modeling of cardiovascular diseases, toxicology testing and ultimately for cardiovascular regenerative cell therapy. We propose to use a novel robust and efficient iPS methodology which employs a cocktail of small molecule inducers, termed "Chemically induced Pluripotent Stem (CiPSC), eliminating the need for any exogenous gene transduction (i.e. a major impediment of iPS methodologies described by others). In this proposal, feasibility of this approach will be demonstrated via derivation of cardiomyocytes (CiPSC-CM) using well established procedures for in-vitro derivation of cardiomyocytes from iPS and hESC. These CiPSC are obtained without any abnormal and permanent modifications to the cellular and molecular machinery typically observed by other DNA vector induced iPS methodologies. Our long-term goals (Phase II and beyond) are to use CiPSC-CMs in generating host- compatible CM replacement therapy, producing in-vitro disease-specific model and facilitating in-vitro therapeutic and toxicity screen in animal and human model systems. PUBLIC HEALTH RELEVANCE: Human stem cells generated by induced direct reprogramming of adult somatic cells, termed induced pluripotent stem (iPS) cells, offer "paradigm shifting" opportunities for studying human disease specific/ personalized models, and provide a personalized renewable source of cells for practical autologous cell therapies, regenerative medicine, and predictive toxicology applications. The possibility of using iPS cells as a tool for development of such patient and disease specific model systems, however, remains at best challenging and stills a clear unmet need due to the shortcomings in this field. Studies outlined in this proposal are designed to explore application of Chemically induced Pluripotent Stem Cells (CiPSC) for the generation of personalized cardiomyocytes which can be used for modeling of cardiovascular diseases, toxicology testing and ultimately for cardiovascular regenerative cell therapy. CiPSC eliminates the need for any exogenous gene transduction, which is a major impediment of iPS methodologies described to date by others.